Immuno-metabolic reprogramming of T cell: a new frontier for pharmacotherapy of Rheumatoid arthritis.

Rheumatoid arthritis (RA) is a persistent autoimmune condition characterized by ongoing inflammation primarily affecting the synovial joint. This inflammation typically arises from an increase in immune cells such as neutrophils, macrophages, and T cells (TC). TC is recognized as a major player in RA pathogenesis. The involvement of HLA-DRB1 and PTPN-2 among RA patients confirms the TC involvement in RA. Metabolism of TC is maintained by various other factors like cytokines, mitochondrial proteins & other metabolites. Different TC subtypes utilize different metabolic pathways like glycolysis, oxidative phosphorylation and fatty acid oxidation for their activation from naive TC (T0). Although all subsets of TC are not deleterious for synovium, some subsets of TC are involved in joint repair using their anti-inflammatory properties. Hence artificially reprogramming of TC subset by interfering with their metabolic status poised a hope in future to design new molecules against RA.

Pioglitazone attenuate level of myeloperoxidases and nitic oxide in psoriatic lesion: a proof-of-concept study in a imiquimod induced psoriasis model in rat.

OBJECTIVES: Psoriasis is a persistent autoimmune inflammatory condition that is primarily affecting the skin. Pioglitazone (PGZ), a peroxisome proliferator activated receptor gamma (PPARγ) agonist, has been reported to have anti-inflammatory effects. However, the role of PGZ in psoriatic disease remains unclear. In this study, we aimed to repurpose the use of the PGZ for the treatment of psoriasis. METHODS: To investigate its efficacy, we employed an imiquimod (IMQ)-induced rat model. Wistar rats are randomly allocated to four different groups. Group, I served as a negative control, Group II IMQ control, Group III was treated with pioglitazone hydrogel and Group IV received standard drug betamethasone cream. PASI score was monitored on every alternative day and on day 7 animals were sacrificed and histopathology of skin was performed. Level of nitric oxide (NO) and myeloperoxidase (MPO) was also performed using established methods. RESULTS: The results of the experiment revealed that treatment with PGZ significantly (p<0.05) reduced redness, scaling, and skin thickening, surpassing the effectiveness of standard drugs. Our result also indicates that PGZ significantly (p<0.05) inhibits the release of both MPO and NO from the psoriatic lesions. CONCLUSIONS: PGZ effectively reduces the severity of psoriasis possibly by inhibiting the accumulation of neutrophil at the psoriatic area which indirectly regulates the release of NO in the affected area. Our study showed we can repurpose the PGZ for the management of psoriasis.

Artificially induced in situ macrophage polarization: An emerging cellular therapy for immuno-inflammatory diseases.

Macrophages are the mature form of monocytes that have high plasticity and can shift from one phenotype to another by the process of macrophage polarization. Macrophage has several vital pharmacological tasks like eliminating microorganism invasion, clearing dead cells, causing inflammation, repairing damaged tissues, etc. The function of macrophages is based on their phenotype. M1 macrophages are mostly responsible for the body's immune responses and M2 macrophages have healing properties. Inappropriate activation of any one of the phenotypes often leads to ROS-induced tissue damage and affects wound healing and angiogenesis. Therefore, maintaining tissue macrophage homeostasis is necessary. Studies are being done to find techniques for macrophage polarization. But, the process of macrophage polarization is very complex as it involves multiple signalling pathways involving innate immunity. Thus, identifying the right pathways for macrophage polarization is essential to apply the polarizing technique for the treatment of various inflammatory diseases where macrophage physiology influences the disease pathology. In this review, we highlighted the various techniques so far used to change macrophage plasticity. We believe that soon macrophage targeting therapeutics will hit the market for the management of inflammatory disease. Hence this review will help macrophage researchers choose suitable methods and materials/agents to polarize macrophages artificially in various disease models.

Attenuation of COX-2 enzyme by modulating H2O2-mediated NF-κB signaling pathway by monoamine oxidase inhibitor (MAOI): a further study on the reprofiling of MAOI in acute inflammation.

OBJECTIVE: This study aims to investigate the anti-inflammatory mechanism of monoamine oxidase inhibitor (MAOI) in carrageenan (CARR) induced inflammation models to reprofile their use. We also aimed to explore the role of monoamine oxidase (MAO)-mediated H2O2-NF-κB-COX-2 pathway in acute inflammation. METHODS: In vitro anti-inflammatory activity and hydrogen peroxide (H2O2) scavenging activity were performed according to the established procedure. Inflammation was induced using CARR in BALB/c mice at the foot paw and peritoneal cavity. Hourly measurement of paw swelling was performed. The level of nitric oxide (NO), myeloperoxidase (MPO), cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2) and nuclear factor κB (NF-κB) was determined using enzyme-linked immunosorbent assay (ELISA). Peritoneal fluid was collected to investigate total count, differential count of leukocytes, and capillary permeability. RESULTS: In vitro anti-inflammatory evaluations revealed the potential role of MAOI to inhibit heat-induced protein denaturation and human red cell membrane destabilization. H2O2 inhibition activity of MAOI also proved their powerful role as an H2O2 scavenger. Treatment with MAOI in CARR-induced mice significantly reduced paw edema, leukocyte extravasation, and total and differential leukocyte count. The result of ELISA showed MAOI effectively reduce the level of COX-2, PGE2 and NF-κB in inflamed tissue. CONCLUSIONS: In short, this study demonstrates that inhibition of H2O2 by MAOI alleviates CARR-induced paw edema possibly by inhibiting the H2O2-mediated NF-κB-COX-2 pathway. The present investigation identifies MAOI might reprofile for the treatment of acute inflammation also, the MAO enzyme may use as a novel therapeutic target to design and develop new class of anti-inflammatory agents.

Role of Macrophage in Type 2 Diabetes Mellitus: Macrophage Polarization a New Paradigm for Treatment of Type 2 Diabetes Mellitus.

Metabolic diseases such as type 2 diabetes mellitus are usually associated with meta-inflammation. ß-cell failure is a marked feature observed in the pathogenesis of type 2 diabetes mellitus. Type 2 diabetes mellitus (T2DM) is a heterogeneous situation that is accompanied by not only defective insulin secretion but also peripheral insulin resistance. ß-cells are the primary organ for insulin secretion; hence, it is crucial to maintain a significant ß-cell mass in response to a variety of changes. Insulin resistance is a chief cause of T2DM, leading to increased free fatty acid (FFA) levels, which in turn elevates ß-cell mass and insulin secretion as compensation for insulin insensitivity. It has recently been established that amplified numbers of innate immune cells, cytokines, and chemokines result in detrimental effects on islets in chronic conditions. Macrophage migration inhibitory factor (MIF) is the lymphokine that prevents arbitrary migration of macrophages and assembles macrophages at inflammatory loci. Inflammation is known to trigger monocytes to differentiate into macrophages. Progress of complications associated with type 2 diabetes mellitus, as indicated through recent findings, is also dependent on the buildup of macrophages in tissues vulnerable to diabetic injury. The present article scientifically evaluates the present knowledge concerning the mechanisms of monocyte and macrophage-mediated injury recruitment in complications associated with type 2 diabetes mellitus. It also describes some of the established and experimental therapies that might bring about a reduction in these inflammatory complications. Recent discoveries in the field of drug delivery have facilitated phenotype-specific targeting of macrophages. This review highlights the pathophysiology of type 2 diabetes mellitus, how macrophage induces type 2 diabetes mellitus and potential therapeutics for type 2 diabetes mellitus via macrophage-specific delivery.

Pathophysiology Associated with Diabetes-induced Tauopathy and Development of Alzheimer's Disease.

Alzheimer's disease (AD) is the most common type of dementia that affects the elderly around the world. Chronic type 2 diabetes (T2DM) has been proven to be closely related to neurodegeneration, especially AD. T2DM is characterized by the cell's failure to take up insulin as well as chronic hyperglycemia. In the central nervous system, insulin plays vital regulatory roles, while in chronic hyperglycemia, it leads to the formation and accumulation of advanced glycation end products (AGEs). Inflammation plays a crucial role in development of insulin resistance in AD and T2DM. The microtubule-related protein tau is involved in the pathogenesis of several neurological diseases known as tauopathies, and is found to be abnormally hyperphosphorylated in AD and accumulated in neurons. Chronic neuroinflammation causes the breakdown of the blood-brain barrier (BBB) observed in tauopathies. The development of pro-inflammatory signaling molecules, such as cytokines, chemokines from glial cells, neurons and endothelial cells, decides the structural integrity of BBB and immune cell migration into the brain. This review highlights the use of antidiabetic compounds as promising therapeutics for AD, and also describes several new pathological molecular mechanisms associated with diabetes that increase AD pathogenesis.

Repurposing monoamine oxidase inhibitors (MAOI) for the treatment of rheumatoid arthritis possibly through modulating reactive oxidative stress mediated inflammatory cytokines.

Monoamine oxidase inhibitors (MAOI) are presently used to treat depression, parkinsonian, and other psychiatric disorders. The present study was aimed to repurpose the use of MOAI in Rheumatoid Arthritis (RA). The animal model of RA was developed using collagen type II (CII) in Freund's complete adjuvant (FCA) followed by lipopolysaccharide (LPS) and a booster dose of CII in FCA. The effect of MAOI, Selegiline was evaluated whereas the indicators like paw thickness, arthritic score, and the splenic index were measured and compared with the standard drug Methotrexate. Further to explore the molecular mechanism, the expression of serum inflammatory cytokines (IL-6 and TNF-α), radiographical and histopathological study of hind paw were also checked and analyzed. Treatment with MAOI, Selegiline not only reduced the paw thickness, arthritic score, and the splenic index, but also greatly improved the inflammatory biochemical and hematologic parameters and improved the arthritis score. The serum level of IL-6 and TNF-α are considerably decreased dose dependently, however, the notable significant effect (**p < 0.01) observed at concentration of 30 mg/kg b.w. when the RA animals treated by Selegiline. Collectively, Selegiline improved the progression of RA possibly via decreased catecholamine breakdown at synovial fluid resulting decrease hydrogen peroxide (H2O2) generation and inhibition of pro-inflammatory cytokines in situ. Thus, the finding support and indicate the repurposing of MAOI for the treatment of RA meriting further studies on synovial monoamine oxidase as a new therapeutic target to design a new drug for RA.